EP3926042A4 - Adjuvant pouvant favoriser la multiplication de cellules immunitaires in vivo - Google Patents

Adjuvant pouvant favoriser la multiplication de cellules immunitaires in vivo Download PDF

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Publication number
EP3926042A4
EP3926042A4 EP20755525.1A EP20755525A EP3926042A4 EP 3926042 A4 EP3926042 A4 EP 3926042A4 EP 20755525 A EP20755525 A EP 20755525A EP 3926042 A4 EP3926042 A4 EP 3926042A4
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EP
European Patent Office
Prior art keywords
vivo
immune cells
adjuvant capable
promoting expansion
promoting
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20755525.1A
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German (de)
English (en)
Other versions
EP3926042A1 (fr
Inventor
Weiyue GU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chineo Medical Technology Co Ltd
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Chineo Medical Technology Co Ltd
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Filing date
Publication date
Application filed by Chineo Medical Technology Co Ltd filed Critical Chineo Medical Technology Co Ltd
Publication of EP3926042A1 publication Critical patent/EP3926042A1/fr
Publication of EP3926042A4 publication Critical patent/EP3926042A4/fr
Pending legal-status Critical Current

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/39Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503Immunoglobulin superfamily
    • C07K14/7051T-cell receptor (TcR)-CD3 complex
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14Blood; Artificial blood
    • A61K35/17Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/46Cellular immunotherapy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/46Cellular immunotherapy
    • A61K39/461Cellular immunotherapy characterised by the cell type used
    • A61K39/4611T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/46Cellular immunotherapy
    • A61K39/461Cellular immunotherapy characterised by the cell type used
    • A61K39/4612B-cells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/46Cellular immunotherapy
    • A61K39/461Cellular immunotherapy characterised by the cell type used
    • A61K39/4613Natural-killer cells [NK or NK-T]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/46Cellular immunotherapy
    • A61K39/462Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4622Antigen presenting cells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/46Cellular immunotherapy
    • A61K39/463Cellular immunotherapy characterised by recombinant expression
    • A61K39/4631Chimeric Antigen Receptors [CAR]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/46Cellular immunotherapy
    • A61K39/464Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643Vertebrate antigens
    • A61K39/4644Cancer antigens
    • A61K39/464402Receptors, cell surface antigens or cell surface determinants
    • A61K39/464403Receptors for growth factors
    • A61K39/464404Epidermal growth factor receptors [EGFR]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/46Cellular immunotherapy
    • A61K39/464Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643Vertebrate antigens
    • A61K39/4644Cancer antigens
    • A61K39/464402Receptors, cell surface antigens or cell surface determinants
    • A61K39/464411Immunoglobulin superfamily
    • A61K39/464412CD19 or B4
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503Immunoglobulin superfamily
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503Immunoglobulin superfamily
    • C07K14/70521CD28, CD152
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70596Molecules with a "CD"-designation not provided for elsewhere
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/71Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06Animal cells or tissues; Human cells or tissues
    • C12N5/0602Vertebrate cells
    • C12N5/0634Cells from the blood or the immune system
    • C12N5/0636T lymphocytes
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06Animal cells or tissues; Human cells or tissues
    • C12N5/0602Vertebrate cells
    • C12N5/0634Cells from the blood or the immune system
    • C12N5/0646Natural killers cells [NK], NKT cells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/51Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515Animal cells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/51Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515Animal cells
    • A61K2039/5156Animal cells expressing foreign proteins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/545Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511Organic adjuvants
    • A61K2039/55516Proteins; Peptides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55588Adjuvants of undefined constitution
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00Indexing codes associated with cellular immunotherapy of group A61K39/46
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/60Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622Single chain antibody (scFv)
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • C07K2319/01Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2510/00Genetically modified cells

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Cell Biology (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Wood Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • General Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dermatology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Virology (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
EP20755525.1A 2019-02-11 2020-02-11 Adjuvant pouvant favoriser la multiplication de cellules immunitaires in vivo Pending EP3926042A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910106097.7A CN111544585A (zh) 2019-02-11 2019-02-11 一种可助推免疫细胞在体内扩增的佐剂
PCT/CN2020/074686 WO2020164465A1 (fr) 2019-02-11 2020-02-11 Adjuvant pouvant favoriser la multiplication de cellules immunitaires in vivo

Publications (2)

Publication Number Publication Date
EP3926042A1 EP3926042A1 (fr) 2021-12-22
EP3926042A4 true EP3926042A4 (fr) 2023-08-09

Family

ID=71997981

Family Applications (1)

Application Number Title Priority Date Filing Date
EP20755525.1A Pending EP3926042A4 (fr) 2019-02-11 2020-02-11 Adjuvant pouvant favoriser la multiplication de cellules immunitaires in vivo

Country Status (5)

Country Link
US (1) US20220233589A1 (fr)
EP (1) EP3926042A4 (fr)
JP (1) JP2022520777A (fr)
CN (2) CN111544585A (fr)
WO (1) WO2020164465A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117230006A (zh) * 2022-06-15 2023-12-15 复旦大学附属中山医院 溶血磷脂酰胆碱在促进b细胞增殖方面的应用
CN117624375A (zh) * 2022-08-30 2024-03-01 北京卡替医疗技术有限公司 增强受体、表达增强受体的免疫细胞及其用途

Citations (2)

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WO2016069647A1 (fr) * 2014-10-27 2016-05-06 Fred Hutchinson Cancer Research Center Compositions et procédés pour intensifier l'efficacité de l'immunothérapie cellulaire adoptive
WO2018075794A1 (fr) * 2016-10-19 2018-04-26 City Of Hope Utilisation du vaccin contre le cmv triplex en thérapie par lymphocytes t à car

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EP0859625B1 (fr) * 1995-10-20 2008-06-25 University Of Nebraska Board Of Regents Composition et procedes permettant d'accentuer les reponses immunitaires dues aux cellules presentatrices d'antigene
EP1107789B1 (fr) 1998-08-24 2008-06-25 The Board Of Trustees Of The Leland Stanford Junior University Compositions et procedes pour proteger des organes, tissus et cellules contre des lesions induites par le systeme immunitaire
US6534261B1 (en) 1999-01-12 2003-03-18 Sangamo Biosciences, Inc. Regulation of endogenous gene expression in cells using zinc finger proteins
GB0028319D0 (en) * 2000-11-20 2001-01-03 Univ Southampton Materials and methods relating to fusion proteins for inducing an immune response
CN102586185A (zh) * 2012-03-12 2012-07-18 浙江中赢方舟生物工程股份有限公司 一种k562细胞扩增激活nk细胞的方法
EP2948544A4 (fr) * 2013-01-28 2016-08-03 St Jude Childrens Res Hospital Récepteur chimérique à spécificité nkg2d adapté pour être utilisé en thérapie cellulaire contre le cancer et les maladies infectieuses
JP2017535284A (ja) * 2014-11-05 2017-11-30 ボード・オブ・リージエンツ,ザ・ユニバーシテイ・オブ・テキサス・システム 免疫エフェクター細胞の拡大のための遺伝子改変免疫エフェクター細胞及び遺伝子操作細胞
US11135245B2 (en) * 2014-11-17 2021-10-05 Adicet Bio, Inc. Engineered γδ T-cells
JP7269733B2 (ja) * 2015-06-12 2023-05-09 レンティジェン・テクノロジー・インコーポレイテッド 操作されたt細胞を用いて癌を処置するための方法
WO2017015427A1 (fr) * 2015-07-21 2017-01-26 Novartis Ag Méthodes pour améliorer l'efficacité et l'expansion de cellules immunitaires
JP6884155B2 (ja) * 2016-02-18 2021-06-09 エンリヴェックス セラピューティクス リミテッド 癌治療のための併用免疫療法及びサイトカイン制御療法
CN105906705A (zh) * 2016-06-19 2016-08-31 苏州普罗达生物科技有限公司 一种cd19免疫原多肽及其用途
WO2018111340A1 (fr) * 2016-12-16 2018-06-21 Novartis Ag Procédés de détermination de la puissance et de la fonction proliférative de lymphocytes t à récepteur antigénique chimérique (car)
MX2020000900A (es) * 2017-07-29 2021-01-08 Juno Therapeutics Inc Reactivos para expandir celulas que expresan receptores recombinantes.
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WO2016069647A1 (fr) * 2014-10-27 2016-05-06 Fred Hutchinson Cancer Research Center Compositions et procédés pour intensifier l'efficacité de l'immunothérapie cellulaire adoptive
WO2018075794A1 (fr) * 2016-10-19 2018-04-26 City Of Hope Utilisation du vaccin contre le cmv triplex en thérapie par lymphocytes t à car

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Title
CHEUNG ALEXANDER S ET AL: "Scaffolds that mimic antigen-presenting cells enable ex vivo expansion of primary T cells", NATURE BIOTECHNOLOGY, NATURE PUBLISHING GROUP US, NEW YORK, vol. 36, no. 2, 15 January 2018 (2018-01-15), pages 160 - 169, XP036978439, ISSN: 1087-0156, [retrieved on 20180115], DOI: 10.1038/NBT.4047 *
DREW C DENIGER ET AL: "Bispecific T-cells Expressing Polyclonal Repertoire of Endogenous γδ T-cell Receptors and Introduced CD19-specific Chimeric Antigen Receptor", MOLECULAR THERAPY, vol. 21, no. 3, 1 March 2013 (2013-03-01), US, pages 638 - 647, XP055278535, ISSN: 1525-0016, DOI: 10.1038/mt.2012.267 *
PALLAVI V. RAJA MANURI ET AL: "piggyBac Transposon/Transposase System to Generate CD19-Specific T Cells for the Treatment of B-Lineage Malignancies", HUMAN GENE THERAPY, vol. 21, no. 4, 1 April 2010 (2010-04-01), pages 427 - 437, XP055181368, ISSN: 1043-0342, DOI: 10.1089/hum.2009.114 *
See also references of WO2020164465A1 *

Also Published As

Publication number Publication date
CN113811602A (zh) 2021-12-17
US20220233589A1 (en) 2022-07-28
EP3926042A1 (fr) 2021-12-22
CN111544585A (zh) 2020-08-18
JP2022520777A (ja) 2022-04-01
WO2020164465A1 (fr) 2020-08-20

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